Morad, H.O.J., Luqman, S., Garcia Pinto, L., Cunningham, K., Vilar, B., Clayton, G., Shankar-Hari, M. and McNaughton, P.A. 2022. Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release. Scientific Reports. 2022 (12) 11078. https://doi.org/10.1038/s41598-022-15214-6
| Title | Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release |
|---|---|
| Type | Journal article |
| Authors | Morad, H.O.J., Luqman, S., Garcia Pinto, L., Cunningham, K., Vilar, B., Clayton, G., Shankar-Hari, M. and McNaughton, P.A. |
| Abstract | Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death. |
| Keywords | Biophysics |
| Cell biology | |
| Immunology | |
| Medical research | |
| Drug discovery | |
| Article number | 11078 |
| Journal | Scientific Reports |
| Journal citation | 2022 (12) |
| ISSN | 2045-2322 |
| Year | 2022 |
| Publisher | Nature Publishing Group |
| Publisher's version | License CC BY 4.0 File Access Level Open (open metadata and files) |
| Digital Object Identifier (DOI) | https://doi.org/10.1038/s41598-022-15214-6 |
| PubMed ID | 35773325 |
| Web address (URL) | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9245885/ |
| Publication dates | |
| Published | 30 Jun 2022 |
| Supplemental file | File Access Level Open (open metadata and files) |